Opinion
EDITORIAL
Immunosuppression and Secondary Infection in Sepsis
Part, Not All, of the Story
Derek C. Angus, MD, MPH; Steven Opal, MD
Despite considerable efforts to promote early identification
and treatment of sepsis, each year several million individu-
als worldwide develop sepsis-induced multiple organ dys-
function, requiring admis-
sion to intensive care and
Related article page 1469 institution of life support,
and frequently progressing
to death or protracted illness and incomplete recovery. Sep-
sis is now the leading cause of death in US hospitals and is
projected to account for more than 5 million deaths globally
each year.1,2 The question is why. More specifically, why do
patients with sepsis who receive appropriate antibiotics and
prompt institution of life support still die? Certainly, there
are instances when life support is inadequate, such as over-
whelming shock unresponsive to fluids and vasopressors or
severe hypoxia despite advanced mechanical ventilatory
support. However, many critically ill patients simply lie in an
ICU bed receiving life support while the team monitors for
complications, titrates life support treatment, and waits to
see what transpires.
This clinical conundrum has not gone unnoticed. Research-
ers have relentlessly pursued the mechanisms of persistent
critical illness, postulating numerous theories. For many years,
the prevailing theory was that organs were impaired by an over-
active or hyperinflammatory innate immune response and its
effect on regional and local blood flow, endothelial function,
and parenchymal cellular energy uptake and metabolism. How-
ever, recent work has focused on a more complex understand-
ing of how dysfunction in both the innate and adaptive im-
mune systems may contribute to poor outcomes in sepsis.
Specifically, the finding that patients appeared to be more sus-
ceptible to secondary infections, coupled with observations
of blunted immune responses to microbial challenges, such as
decreased major histocompatibility complex class 2 antigen
expression on the surface of circulating white blood cells, led
researchers to speculate that the immune system could
become hypoactive or “paralyzed.”3
Two broad uncertainties complicate validation of this
theory. First, the immune system is protean, and the degree
to which patterns of immune function and dysfunction occur
over time, involve its many components, and are uniform in
all patients or in select, identifiable subsets is unknown.
Second, the initial contention that suppressed immunity leads
to secondary infection, which in turn leads to increased
mortality and morbidity, is not well established in sepsis.
The JAMA article by van Vught and colleagues4 attempts
to shed light on these 2 issues. Specifically, the authors first
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sought to determine the incidence and attributable mortality
of secondary infections among 1719 ICU admissions with a
diagnosis of sepsis. Second, the authors attempted to deter-
mine whether these infections were associated with clinical
risk factors or host genomic immune response patterns. The
project was part of the European Union–funded Molecular
Diagnosis and Risk Stratification of Sepsis (MARS) program
and rested principally on the construction of a prospective
cohort of ICU patients at 2 large academic medical centers in
the Netherlands. Importantly, the investigators invested
considerable effort in careful clinical phenotyping, both to
determine whether ICU patients met criteria for sepsis on
admission and to determine the occurrence of secondary
infections and other noninfectious complications.5 In addi-
tion, in a subset of patients diagnosed with sepsis (n = 421),
the investigators also determined gene expression in circu-
lating white blood cell gene expression at the time of
ICU admission and again on the day that infectious and
noninfectious complications occurred.
There were 232 admissions (13.5%) for sepsis whose ICU
course was complicated by a secondary infection. Although
patients who developed secondary infection had a much
higher 60-day mortality rate (44.2% vs 29.1%, P < .001), this
difference was largely explained by the fact that patients
who developed secondary infections were also sicker on
admission (Acute Physiology and Chronic Health Evaluation
IV [APACHE IV] scores 90 vs 79, P < 001). In analyses that
accounted for baseline differences and for competing risks
over time of developing an infection, being discharged, or
dying, the attributable mortality fraction of secondary infec-
tion was relatively modest, accounting for only 10.9% by
day 60 (P = .03), which represents an absolute increase in
mortality of only 2%.
The gene expression patterns among patients with sepsis
at the time of ICU admission were markedly different from
those of healthy controls, showing broad up-regulation of both
proinflammatory and anti-inflammatory molecules and down-
regulation of multiple adaptive immunity pathways, similar
to that seen in other patients with major injury or sepsis.6 Im-
portantly, the authors were unable to detect differences at base-
line between patients who would later develop an ICU infec-
tion or not. However, paired analyses comparing gene
expression at baseline to that on the day a secondary infec-
tion developed showed that circulating white blood cells had
developed expression profiles reflective of reduced glycoly-
sis and gluconeogenesis. Glycolysis is characteristically used
by tumor cells to enhance energy production via conversion
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 Opinion Editorial
of glucose to lactate despite normal levels of oxygen (the
Warburg effect). Recent experimental evidence suggests
immune cells, following epigenetic reprogramming, also rely
on the Warburg effect to fully mount an inflammatory
response.7 In contrast, the paired analyses of patients with sep-
sis who developed noninfectious complications showed no
such changes over time.
The pattern of secondary infections among ICU admis-
sions for reasons other than sepsis was generally similar to that
seen in sepsis admissions. The rate of secondary infections was
15.1% (291 of 1921 admissions), infections were more com-
mon in patients with more severe illness, as evidenced by
higher APACHE IV scores, and the attributable mortality
fraction by day 60 was 21.1% (95% CI, 0.6%-41%, P < .05),
representing a 2.8% absolute increase.
Several strengths of this innovative study are worthy of
mention. This is the largest transcriptome analysis of criti-
cally ill ICU patients with sepsis and without sepsis in whom
the incidence and features of secondary ICU infections were
specifically studied. A clinically well-characterized, carefully
phenotyped, adult ICU patient population complements the
gene expression data. The authors were thoughtful with re-
gard to their use of competing risk models, and their sensitiv-
ity analyses were reassuring in suggesting that their findings
were robust to alternative decisions regarding whether the unit
of analysis was patients or admissions, or restricted only to first
admissions. Their primary findings focus on differences within
the sepsis cohort, but there is added value in including a non-
sepsis comparator group, and here the investigators chose a
well-matched, contemporary patient population of ICU
patients without sepsis.
In retrospect, some features of the design deserve
consideration. Numerous measured and unmeasured poten-
tial confounders could complicate both the clinical and tran-
scriptome analyses. Perhaps if the patients were more homo-
geneous, including only direct, first-time admissions to the
ICU with a single cause of sepsis (eg, severe community-
acquired, pneumococcal pneumonia), then the genomic sig-
natures may have been more uniform, allowing better isola-
tion of subtle differences among patients who would later
succumb to secondary infection. The gene expression pro-
files are dynamic, and susceptible to the choice of antibiotic
and the many other drugs such patients receive (eg, opiates,
drugs for metabolic syndrome, nonsteroidal and steroidal
anti-inflammatory drugs, and statins), and other nonpharma-
cologic organ support strategies. The findings also may not
generalize beyond this northern European country with
ready access to ICU beds, first-rate infection control services,
and a low rate of multidrug -esistant pathogens. In addition,
this study, and all such studies in humans, can provide only
limited causal inference because neither the inciting event,
sepsis, nor the intermediate events, such as organ failure or
secondary infection, can be assigned randomly.
Despite these potential limitations, the study findings have
several important implications. First, secondary infections oc-
cur at a reasonably frequent rate in both patients with sepsis
and other critically ill patients, especially among those who
are most severely affected at the time of ICU admission, but
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the overall contribution of secondary infections to short-
term mortality is quite modest. It is possible that the effect of
secondary infections could be higher in other settings, but strat-
egies that effectively reduce these infections will likely only
reduce some and by no means all of the morbidity and
mortality following sepsis.
Second, the finding of diminished glucose metabolism in
circulating white blood cells at the onset of secondary infec-
tion supports the theory that these infections arise because of
acquired immune dysfunction. Oxidative phosphorylation
gives way to up-regulated anaerobic glycolysis in myeloid cells
during acute infections. Failure to alter glucose metabolism
appropriately early in the course of an infection might signify
an impaired host response to infection.7 However, the study
by van Vught et al did not include sequential gene expression
studies in all patients, and so the frequency and timing of this
Warburg-like metabolic change over time remains unclear.
Nevertheless, strategies to both monitor and to manipulate im-
mune cell metabolism could be promising. What is unclear is
whether manipulating these metabolic effects could yield
benefits beyond mitigation of secondary infection.
Third, the gene expression profile showed broad general-
ized changes that were consistent with host response to injury
but were not predictive at baseline of the risk of secondary in-
fection. The human host, like many other species, has only a
limited repertoire of pattern recognition receptors of the in-
nate immune system to detect both pathogen-associated and
damage-associated molecular patterns. Molecular pattern rec-
ognition triggers a somewhat common signaling apparatus to
activate the innate immune response and trigger downstream
signaling to the adaptive immune system. Thus, it is perhaps
not surprising that gene expression profiles of circulating white
blood cells are similar at the onset of infection-induced tissue
injury or other causes of tissue injury, necrosis, or excess apop-
tosis. In turn, this similarity also helps to explain the similar clini-
cal features. Of note, different baseline clinical and immuno-
logic patterns have been associated with differences in
mortality.6,8 However, a strong causal link connecting unique
baseline clinical or immunologic patterns to specific interme-
diate events, such as secondary infection, and, in turn, to death
or long-term morbidity, remains elusive.
Thus, the study by van Vught and colleagues provides both
encouraging and discouraging findings in the challenge of sep-
sis. Early hopes that immune suppression would be a unify-
ing and common feature of all patients with sepsis who have
poor outcomes are not supported by this study. However,
immune dysfunction does appear to have an important role
in a subset of patients. At least 4 experimental agents are being
tested in clinical trials to reconstitute immune responsive-
ness in critically ill patients, including granulocyte-
macrophage colony-3 stimulating factor (NCT00252915),
interleukin 7 (NCT02640807), anti-programmed cell death
ligand 1 (NCT02576457), and thymosin (NCT00711620). The
key challenges underscored by this study will be proper patient
selection, which will require study designs that can test the
performance of putative clinical and transcriptomic biomarkers
of immune dysfunction, and choosing realistic goals for
treatment outcomes.
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ARTICLE INFORMATION
Author Affiliations: Department of Critical Care
Medicine, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania (Angus); Clinical
Research, Investigation, and Systems Modeling of
Acute illness (CRISMA) Center, Pittsburgh,
Pennsylvania (Angus); Associate Editor, JAMA
(Angus); Division of Infectious Diseases,
Department of Medicine, Alpert Medical School of
Brown University School of Medicine, Providence,
Rhode Island (Opal).
Corresponding Author: Derek C. Angus, MD, MPH,
Department of Critical Care Medicine, University of
Pittsburgh, 3550 Terrace St, 614 Scaife Hall,
Pittsburgh, PA 15261 (angusdc@upmc.edu).
Published Online: March 15, 2016.
doi:10.1001/jama.2016.2762.
Conflict of Interest Disclosures: Both authors
have completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Angus reports personal fees from Ferring
Pharmaceuticals, outside the submitted work; and
NIH funding for a planning grant to design an
evaluation of anti-PDL1 therapy for sepsis,
consulting fees from Beckman Coulter, Biocartis NV,
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GenMark Diagnostics, GlaxoSmithKline, and Ibis
Biosciences for general advice he provided on study
design and diagnostic and therapeutic
development in sepsis. Dr Opal reports grants from
Asahi-Kasei, Cardeas, and Biocartis and personal
fees from Arasnis, Aridis, BioAegis, Cyon, Battell,
Atoxbio, and Becton-Dickinson.
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(Reprinted) JAMA April 12, 2016 Volume 315, Number 14
Editorial Opinion
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